Abstract
Brg1/SMARCA4 serves as the ATPase and the helicase catalytic subunit for the multi-component SWI/SNF chromatin remodeling complex, which plays a pivotal role in governing chromatin structure and gene transcription. However, the upstream signaling pathways regulating Brg1 protein stability and its physiological contribution to carcinogenesis remain largely elusive. Here we report that Brg1 is a bona fide ubiquitin substrate of SCFFBW7. We reveal that CK1δ phosphorylates Brg1 at Ser31/Ser35 residues to facilitate the binding of Brg1 to FBW7, leading to ubiquitination-mediated degradation. In keeping with a tumor suppressive role of FBW7 in human gastric cancer, we find an inverse correlation between FBW7 and Brg1 expression in human gastric cancer clinical samples. Mechanistically, we find that stabilization of Brg1 in gastric cancer cells suppresses E-cadherin expression, subsequently promoting gastric cancer metastasis. Hence, this previously unknown FBW7/Brg1 signaling axis provides the molecular basis and the rationale to target Brg1 in FBW7-compromised human gastric cancers.
Highlights
Brg1/SMARCA4 serves as the ATPase and the helicase catalytic subunit for the multicomponent SWI/SNF chromatin remodeling complex, which plays a pivotal role in governing chromatin structure and gene transcription
We investigated the relationship of Brg[1] and FBW7 in human gastric cancer cell lines and found that Brg[1] expression was inversely correlated with the expression of FBW7 (Supplementary Figure 1c)
There are three FBW7 isoforms identified in human genome (α, β, and γ)[20], to determine if there is any specificity for FBW7 isoforms to interact with, and to promote Brg[1] ubiquitination, we examined the expression of three isoforms in gastric cancer cells and revealed FBW7α as the most abundant isoform (Supplementary Figure 2a)
Summary
Brg1/SMARCA4 serves as the ATPase and the helicase catalytic subunit for the multicomponent SWI/SNF chromatin remodeling complex, which plays a pivotal role in governing chromatin structure and gene transcription. In keeping with an important role for the SWI/SNF chromatin remodeling complex in tumorigenesis, Brg[1] is frequently mutated or deleted in various types of human cancers including non-small-cell lung cancer and ovarian small cell carcinoma[5,6,7,8] In these cancer types, mutations in Brg[1] display loss of function phenotypes and Brg[1] appears to function as a tumor suppressor in these tissue settings. Understanding the molecular mechanism that drives the metastasis event in gastric cancer becomes more imperative and significant, which may provide the molecular basis to design novel targeted therapy for this deadly disease To this end, the expression of FBW7, a bona fide tumor suppressor and a substrate recognition subunit of the SCFFBW7 E3 ubiquitin ligase complex[20], was found to be decreased in gastric cancer at mRNA levels[21,22]. In this study, we further explored whether Brg[1] overexpression in gastric cancer is in part due to FBW7 reduction or loss and mechanistically how the FBW7/Brg[1] signaling axis contributes to tumor metastasis and poor outcome of gastric cancer patients
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